Case Studies: Application ofPharmacokinetic Modeling toInform Water MonitoringInformWaterMonitoringMonitoringPresentation to the FIFRA Scientific Advisory PanelJuly 26-29, 2011Chester RodriguezChesterRodriguezNelson ThurmanUSEPA Office of Pesticide ProgramsUSEPAOfficeofPesticideProgramsOutline•How did we get here? (C. Rodriguez)P d i i d i (C R d i )•Proposedwater monitoringdurations(C.Rodriguez)•Estimating drinking water exposure from monitoringsampled at weekly intervals (N Thurman)sampledatweeklyintervals(N.Thurman)•Estimates for 1995 Maumee R•Estimates for 2007 MO-01•Estimating human plasma AUC from drinking waterexposures (C. Rodriguez)•Estimates for 1995 Maumee R•Estimates for 2007 MO-01•Summary (C. Rodriguez)2Summary(C.Rodriguez)152025

i ng Hormone m (ng/ml)Repeateddailydosingover4daysCooperetal.20104681 mg/kg bw ATRA3 mg/kg bw ATRA7 mg/kg bw ATRA10 mg/kg bw ATRA

m a Triazines (mg/L)PK Profile of Radiolabeled TriazinesVehicle1.563.126.2512.5250510Atrazine (mg/kg-d)

Leutiniz i

Seru m024487296120144168192216240264288024start of dosingpseudosteady state dosing stoppedtime (hrs)

Radiolabeled Plas m024Paul et al. 1993

e led triazines(ppm))LinearEliminationKinetics100012501500y= 13.0x - 8.57R2= 0.994

d aily e AUC h)AUC Scales with Atrazine Dose(Doserate)tAUCforratLH4896144192240288336384-4-20time (hr)

ln (Plasma radiolab e0204060801000250500750ATRA dose (mg/kg/day)

pseudo

d steady stat (mg/L-(Doserate)ratVdssrat*kelratAUCforratLHattenuation=Plasma Triazines(Cp, mg/L)kel(hr‐1)TriazineseliminatedAtrazine(mg)Vdss(L)One‐compartmentlinearmodelAve. water levelsAUC=(Doserate)humanVdsshuman*kelhumanDose rate(μg/L)Water consumptionWaterconsumption(L/day)3Range of Windows of Exposure•4, 14, and 28 days•4-day duration:•Accumulation of plasmatriazinesto steady state seems to be relatedAccumulationofplasmatriazinestosteadystateseemstoberelatedto maximal LH attenuation• Based on a constant dose level and frequency, time to steady state inthe rat is 4 daystheratis4days• Length of the rat estrous cycle•28-day duration:• Within the allometrically scaled time range for adult humans of 60 kgto reach steady state based on aconstant dose level and frequency• 28 days also the average length of the human menstrual cyclegg y•14-day duration:• Serves as midpoint given the other durations• Reasonable to include given thathuman exposure is neither at aconstant dose level nor constant frequency4Estimating Drinking Water Exposure FromMonitoring Sampled at Weekly IntervalsMonitoringSampledatWeeklyIntervalsMonitoringSampledIntervals•Used 2 monitoring data sets with daily samplingUsed2monitoringdatasetswithdailysamplingduring the high use/runoff period• Simulated sampling at 7-day intervals from this data•Used geostatistical methods to develop avariogram model that captures the covariance ofmonitoring data over time based on 7-daymonitoringdataovertimebasedon7sampling intervals•Ran 1,000 conditional simulations of thei d l t ti t d il ti icovariance modelto estimatedailytime seriesfrom the 7-day sampling intervals•Bracketed the 5th-95thpercentiles of the•Bracketedthe5-95percentilesoftheconditional simulations from the 7-day intervals5Estimates for 2007 MO-01 Sampled atWeekly Intervals100D il Ti S iSi95th%il1004Day AveragesSi95th%il60708090

i on, ug/LDailyTimeSeriesSim95th%ileSim5th%ileActual60708090

tion, ug/L4-DayAveragesSim95th%ileSim5th%ileActual2030405060

A trazine Concentrat i2030405060

Atrazine Concentra0102091 98 105 112 119 126 133 140 147 154 161 168 175 182 189

AJulianDay0102091 98 105 112 119 126 133 140 147 154 161 168 175 182 189JulianDay10014-Day AveragesSim95th%ile10028Day AveragesSim95th%ile60708090

a tion, ug/L14-DayAveragesSim95th%ileSim5th%ileActual60708090

a tion, ug/L28-DayAveragesSim95th%ileSim5th%ileActual2030405060

Atrazine Concentr a2030405060

Atrazine Concentr a0102091 98 105 112 119 126 133 140 147 154 161 168 175 182 189JulianDay0102091 98 105 112 119 126 133 140 147 154 161 168 175 182 189JulianDay6Estimates for 1995 Maumee RiverSampled at WeeklyIntervalsEstimates for 1995 Maumee RiverSampled at WeeklyIntervals16D il Ti S iSi95th%il164Day AveragesSi95th%ilp y101214

on, ug/LDailyTimeSeriesSim95th%ileSim5th%ileActual101214

a tion, ug/L4-DayAveragesSim95th%ileSim5th%ileActual468

A trazine Concentrati468

Atrazine Concentr a0291 98 105 112 119 126 133 140 147 154 161 168 175 182 189

AJulianDay0291 98 105 112 119 126 133 140 147 154 161 168 175 182 189JulianDay1614-Day AveragesSim95th%ile1628-Day AveragesSim95th%ile101214

a tion, ug/L14-DayAveragesSim95th%ileSim5th%ileActual101214

a tion, ug/L28-DayAveragesSim5th%ileActual468

Atrazine Concentr a468

Atrazine Concentr a0291 98 105 112 119 126 133 140 147 154 161 168 175 182 189JulianDay0291 98 105 112 119 126 133 140 147 154 161 168 175 182 189JulianDay7Estimating Human Plasma AUC fromAtrazineConcentrations in DrinkingConcentrationsinDrinkingWaterAtrazineConcentrationsinDrinkingWater[atrazine levels]ave(μg/L) x water consumption (L/day)kel (hr-1) x Vdss (L)=Human PlasmaAve. Daily AUCRat Plasma PoD AUC for LH attenuationPredicted human plasma ave. daily AUCInternal MeasureMargin of Exposure=8Rolling Average Human Plasma AUC Valuesfor the 2007 MO-01 Monitoring DataMO-01: daily sampling0.25actual (daily sampling)BMDL AUC/100x

g /L)*h)MO-01: 4-d rolling averages0.25actual 4-d rolling aveBMDL AUC/100x

g /L)*h)0 050.100.150.20actual(dailysampling)Sim 95%ile (weekly sampling)Sim 5%ile (weekly sampling)BMDL AUC/300x

p lasma AUC ((m g0 050.100.150.20actual4 drollingaveSim 95%ile (weekly sampling)Sim 5%ile (weekly sampling)BMDL AUC/300x

plasma AUC ((m g1001101201301401501601701801902000.000.05Julian Day

human p1001101201301401501601701801902000.000.05Julian Days

humanMO-01: 14-d rolling averages0.25actual(14-d rollingave)BMDL AUC/100x

L)*h)MO-01: 28-d rollingaverages0.25BMDL AUC/100x

L)*h)0.100.150.20( g)Sim 95%ile (weekly sampling)Sim 5%ile (weekly sampling)BMDL AUC/300x

l asma AUC ((mg/0.100.150.20Sim95%ile (weekly sampling)Sim 5%ile (weekly sampling)actual (28-d rolling ave)BMDL AUC/300x

l asma AUC ((mg/1001101201301401501601701801902000.000.05Julian Days

human p l901001101201301401501601701801902000.000.05Julian Days

human p l9Estimates of Rolling Human PlasmaAverage Daily AUC ValuesMaumee 95: Daily Sampling0 150.200.25actual (daily sampling)BMDL AUC/100x

((mg/L)*h)Maumee 95: 4-day rollingaverages0.200.25BMDL AUC/100xactual 4-day rolling ave.Sim 95%ile (weekly sampling)

((mg/L)*h)0 000.050.100.15Sim 95%ile (weekly sampling)Sim 5%ile (weekly sampling)BMDL AUC/300x

u man plasma AUC0 000.050.100.15BMDL AUC/300xSim95%ile(weeklysampling)Sim 5%ile (weekly sampling)

u man plasma AUC1001101201301401501601701801902000.00Julian Day

H u1001101201301401501601701801902000.00Julian Days

H uMaumee 95: 14-d rolling averages0.150.200.25actual 14-d rolling aveSim95%ile (weekly sampling)Sim5%ile (weekly sampling)BMDL AUC/100x

U C ((mg/L)*h)Maumee 95: 28-d rolling averages0.150.200.25Sim95%ile (weekly sampling)Sim5%ile (weekly sampling)actual 28-d rolling aveBMDL AUC/100x

U C ((mg/L)*h)1001101201301401501601701801902000.000.050.10Sim5%ile(weeklysampling)BMDL AUC/300x

Human plasma A U1001101201301401501601701801902000.000.050.10BMDL AUC/300x

Human plasma A UJulian Days100110120130140150160170180190200Jilian Days10Summary of Pharmacokinetic Modelingto Inform Water Monitoring•Based on an internal dose metric (AUC) consistentwith temporality of LH attenuationwithtemporalityofLHattenuation•AUC accounts for magnitude and duration ofexposure•One compartment model: best available science inthe absence of a fully calibrated and evaluatedPBPK model•One compartment model accounts for bodydistribution and plasma clearance•The higher the water levels, the higher thepredicted human plasma levels for a given duration(linear relationship)11